Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development

Abstract

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

Long-Term Safety of Stimulant Use for ADHD: Findings from Nonhuman Primates

“…Gill et al (2012) administered extended-release MPH or placebo for 12 months to adolescent male monkeys and measured synaptic DA markers in the brain (DA transporters and D2/D3 receptors), vulnerability to cocaine abuse (self-administration paradigm after a 3-5 month washout period), and physical growth and showed no significant effects of MPH on any of these measures. Similar findings were reported by Soto et al (2012) when peri-adolescent male monkeys were treated with either MPH, AMP, or placebo for 18 months and failed to show effects of stimulant treatment on synaptic DA markers in brain (transporters and D2/D3 receptors; they also failed to see changes in AMP-induced DA increases) as well as in physical growth, both when tested shortly after drug discontinuation and 6 months later. Additionally, they did not observe any major effects on cognitive (ie, reaction times, cognitive control) or motor behaviors (spontaneous locomotor activity) after chronic treatment following immediate or prolonged discontinuation.…”

“…They also suggest that they do not sensitize the brain to drug rewards (Gill et al, 2012) nor that they negatively affect cognitive or motor behaviors after discontinuation (Soto et al, 2012).…”

Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty

“…We relied on the antisaccade task, used widely in the human literature for its simplicity, as performance of the task does not require mastery of complex rules requiring extensive instruction but rather the ability to resist a prepotent stimulus and plan a movement away from it (3,4,(35)(36)(37). Our longitudinal study was designed to track the same individuals at different stages to minimize interindividual variability, which is considerable around puberty (38). Inevitably, this means that our subjects had more experience in the task as adults.…”

“…Performance on the antisaccade task exhibits significant improvements in adolescence in humans (3,4) and is impaired in childhood conditions such as attention deficit/hyperactivity disorder (35) and mental illnesses such as schizophrenia, which typically manifest in early adulthood (36,37). Young monkeys are able to master tasks that require response inhibition, such as the stop signal task and the object retrieval detour, and performance has been shown to improve with age around the time of puberty (38). The present findings show that performance in the antisaccade task also improves markedly between puberty and adulthood.…”

Effects of Psychostimulant Drugs on Developing Brain

“…[64][65][66][67] Resus maymunlarıyla ergenlik öncesi dönemde yapılan bir çalışmada uzun dönem oral metilfenidat ya da amfetamin uygulanmasının fizyolojik, davranışsal ya da bilişsel gelişim üzerine etkisinin sınırlı olduğu bildirilmektedir. [68] Hayvan deneylerinde indirek dopamin agonistleri olan kokain ve metamfetaminin antioksidan enzim düzeylerinde değişiklik oluşturarak oksidatif stresi artırdıkları ve dolayısıyla bilişsel ve psikomotor işlevlerde bozulmaya yol açtığı bildirilmektedir. [69] Yakın dönemde yapılan bir çalışmada prenatal dönemde metamfetamine maruz kalan okul çağı çocuklarında inhibitor kontrol becerisinde yetersizlik saptanmıştır.…”